Safety and Efficacy Study of Inhaled Carbon Monoxide to Treat Acute Respiratory Distress Syndrome (ARDS)

Acute respiratory distress syndrome (ARDS) is a devastating disease affecting military,
veteran, and civilian populations. ARDS is a syndrome of severe acute lung inflammation and
hypoxemic respiratory failure with an incidence of 180,000 cases annually in the United
States. Despite recent advances in critical care management and lung protective ventilation
strategies, ARDS morbidity and mortality remain unacceptably high. The lack of specific
effective therapies for ARDS indicates a need for new treatments that target novel pathways.
Carbon monoxide (CO) represents a novel therapeutic modality in ARDS based on data obtained
in experimental models of ARDS over the past decade.

CO has been shown to be protective in experimental models of acute lung injury (ALI) and
sepsis. Furthermore, multiple human studies have demonstrated that experimental
administration of several different concentrations of CO is well tolerated and that low dose
inhaled CO can be safely administered to subjects in a controlled research environment. The
investigators have previously conducted a Phase I trial of low dose iCO in ARDS which
demonstrated that precise administration of low dose iCO (100 and 200 ppm) is feasible,
well-tolerated, and safe in patients with sepsis-induced ARDS.

The purpose of this study is to assess the safety and efficacy of low dose inhaled carbon
monoxide (iCO) therapy in mechanically ventilated patients with ARDS.

Inclusion Criteria:

All intubated patients ≥ 18 years old with ARDS

1. ARDS is defined when all four of the following criteria are met:

1. A PaO2/FiO2 ratio ≤ 300 with at least 5 cm H2O positive end-expiratory airway
pressure (PEEP)

2. Bilateral opacities on frontal chest radiograph (not fully explained by
effusions, lobar/lung collapse, or nodules) within 1 week of a known clinical
insult or new or worsening respiratory symptoms

3. A need for positive pressure ventilation by an endotracheal or tracheal tube

4. Respiratory failure not fully explained by cardiac failure or fluid overload;
need objective assessment (e.g., echocardiography) to exclude hydrostatic edema
if no risk factor present.

2. ARDS onset is defined as the time the last of criteria 1-4 are met. ARDS must persist
through the enrollment time window of 120 hours.

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation
in this study:

1. Age less than 18 years

2. Greater than 120 hours since ARDS onset

3. Pregnant or breastfeeding

4. Prisoner

5. Patient, surrogate, or physician not committed to full support (exception: a patient
will not be excluded if he/she would receive all supportive care except for attempts
at resuscitation from cardiac arrest)

6. No consent/inability to obtain consent or appropriate legal representative not
available

7. Physician refusal to allow enrollment in the trial

8. Moribund patient not expected to survive 24 hours

9. No arterial or central line/no intent to place an arterial or central line

10. No intent/unwillingness to follow lung protective ventilation strategy

11. Severe hypoxemia defined as SpO2 < 95 or PaO2 < 80 on FiO2 ≥ 0.8

12. Hemoglobin < 7.5 g/dL or hemoglobin < 8 g/dL and actively bleeding

13. Subjects who are Jehovah's Witnesses or are otherwise unable or unwilling to receive
blood transfusions during hospitalization

14. Acute myocardial infarction (MI) or acute coronary syndrome (ACS) within the last 90
days

15. Coronary artery bypass graft (CABG) surgery within 30 days

16. Angina pectoris or use of nitrates with activities of daily living

17. Cardiopulmonary disease classified as NYHA class IV

18. Stroke (ischemic or hemorrhagic) or anoxic/hypoxic brain injury or traumatic brain
injury (TBI) within the prior 3 months

19. Burns > 40% total body surface area (TBSA)

20. Severe airway inhalational injury

21. Use of high frequency oscillatory ventilation

22. Use of extracorporeal membrane oxygenation (ECMO)

23. Concomitant use of inhaled pulmonary vasodilator therapy (eg. nitric oxide [NO] or
prostaglandins)

24. Diffuse alveolar hemorrhage from vasculitis

25. Concurrent participation in other investigational drug study